This invention relates to organic chemical synthesis and more specifically to snythesis of pharmaceutical compounds.
The chemical compound 1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-[(1-methylethyl)amino]-2-prop anol, hereinafter referred to as betaxolol, has recently been introduced and proposed for pharmaceutical use in human and veterinary therapy, in the cardiovascular field, mainly as a .beta.-adrenergic blocking agent. It has the chemical formula: ##STR2##
The family of compounds, including betaxolol, of the following general formula 1: ##STR3## where m is an integer from 2 to 5, n is an integer from 1 to 4, and R is a branched alkyl of 3 or 4 carbon atoms, or cycloalkyl of 3 or 4 carbon atoms, racemic and optically active forms thereof, and pharmaceutically acceptable acid addition salts thereof, is described in Canadian Pat. No. 1,072,981 Synthelabo, together with methods for the preparation thereof.
The prior art synthesis of betaxolol starts with the readily available reagent p-hydroxyphenethyl alcohol, of formula: ##STR4## and converts this to the hydrochloride addition salt of betaxolol using a five step sequential synthesis. The more acidic phenolic hydroxyl is chemically blocked with a benzyl moiety e.g. by reaction of the phenoxide with benzyl chloride. In a second step, the hydroxyethyl group is then etherified by reaction with cyclopropylcarbinyl halide to give the desired species for the final product at this position. The phenolic position is then deprotected by hydrogenolysis and the phenolic position re-etherified with epihalohydrin to give a compound of formula: ##STR5## This fourth step product is then reacted with 2-aminopropane to yield betaxolol base. Thus, two of the five steps in the synthesis are the protection and de-protection of the phenolic hydroxyl. Each is a separate and necessary step.
It is an object of the present invention to provide a novel process for the preparation of betaxolol.
It is a further object to provide a process which avoids the costly and potentially hazardous hydrogenolysis of the prior art process described above and has the potential for a reduced number of synthetic steps.
It is a further object of the invention to provide novel chemical compounds useful as intermediates in the synthesis of betaxolol and similar compounds.